Identification and Characterization of Asymmetrically-Expressed Genes

人类大脑皮层最重要的功能特化之一就是坐骨神经的特化 大脑皮层和与之相连的其他皮质下区域。这些区域参与了人类 更高的认知和行为，包括语言。令人惊讶的是，人们对生物过程知之甚少 这是人类胰岛周围皮质区发育的基础，它们的不对称性，以及 其他潜在的模式生物。这项建议是PI功勋奖的延伸，在这项奖中，我们有 通过它们的不对称成功地识别了涉及人类高级认知的关键基因 胰周皮质的表达或浓缩，包括CNTNAP2和其他细胞外黏附 也与神经心理疾病有关的分子。与此同时，我们开发了一部全新的小说 方法来阐明转录组的复杂结构，并成功地将其应用于成人 人脑。我们建议将这些方法与NextGen测序相结合来进行数字化 解剖定义的相互关联的人类语言皮质及其同源物在非人类中的基因表达 灵长类动物。这项工作将把基因产品置于明确的功能背景下，使其能够表征 对人类大脑组织的这一方面最重要的一组基因，而不是依赖于较少的 对后续基因进行优先排序的结构化方法。推测的差异表达基因和关键枢纽 网络中的基因将使用qRT-PCR和原位杂交进行确认。跨物种 在老鼠和非人类灵长类物种中的比较将继续进行，以研究 作为丰富语言相关模块的中心枢纽的基因的进化保守 在成人的大脑皮质中，或在发育中的人类大脑皮层中不对称表达。这将是 洞察这些基因在语言和语言发展和进化中的潜在作用 相关的人类认知特化以及低等物种中这些区域与同源物种的关系 人类的结构。所有这些都将清楚地为人类神经发育障碍的研究提供信息 与言语和语言有关的，例如自闭症或精神分裂症，就像我们和其他人已经做过的那样 演示，并为使用动物模型治疗这些疾病提供适当的背景。

One of the most important functional specializations of the human cerebral cortex is that of the perisylvian cortex and the other subcortical regions with which it is connected. These regions are involved in human higher cognition and behavior, including language. Surprisingly little is known about the biological processes that underlie the development of perisylvian cortical regions in humans, their asymmetry, and presence in other potential model organisms. This proposal is an extension of the Pi's Merit Award, in which we have worked successfully to identify key genes involved in human higher cognition by virtue of their asymmetric expression or enrichment in perisylvian cortex, including CNTNAP2 and other extracellular adhesion molecules that are also related to neuropsychlatric disease. In parallel, we have developed an entirely novel approach to elucidate the complex structure of the transcriptome, and successfully applied this to adult human brain. We propose to apply these methods in conjunction with NextGen sequencing to perform digital gene expression in anatomically defined interconnected human language cortex and its homologues in nonhuman primates. This work will put gene products in a clear functional context, enabling characterization of the set of genes most central to this aspect of human brain organization, rather than relying on less structured means of prioritizing genes for follow-up. Putative differentially expressed genes and key hub genes within the networks will be confirmed using qRT-PCR and In Situ hybridization. Cross species comparisons, in mice and non-human primate species will continue to be performed to investigate the evolutionary conservation of genes that are central hubs of the modules that are enriched in languagerelated cortex in adults, or asymmetrically expressed in the developing human cerebral cortex. This will provide insight into the potential role of these genes in the development and evolution of language and related human cognitive specializations and the relationship of these regions in lower species to homologous human structures. All of this will clearly inform the study of human neurodevelopmental disorders that are related to speech and language, such as autism or schizoprenia, as we and others have already demonstrated, and provide proper context for the use of animal models for these disorders.